JP2022190022A - Eye drop containing water-soluble polymer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel eye drop containing brimonidine.

SOLUTION: An eye drop contains brimonidine and/or a salt thereof, a water-soluble polymer, and benzalkonium chloride, where the content of brimonidine and/or the salt thereof is 0.05 w/v%-0.2 w/v%, the content of the water-soluble polymer is 0.1 w/v%-1.5 w/v%, the content of the benzalkonium chloride is 0.001 w/v%-0.01 w/v%, and a weight ratio between the brimonidine and/or the salt thereof and the benzalkonium chloride is 1: 0.01-0.1.

SELECTED DRAWING: None

COPYRIGHT: (C)2023,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to an eye drop containing a water-soluble polymer, brimonidine and/or a salt thereof, and benzalkonium chloride (hereinafter also referred to as "BAK").

Brimonidine is a selective adrenergic α2 receptor agonist that suppresses the production of aqueous humor and promotes the outflow of aqueous humor through the uveoscleral outflow tract, thereby reducing intraocular pressure. show. Brimonidine and its salts are therefore used in the treatment of glaucoma.

In order to increase the bioavailability of pharmacological ingredients contained in eye drops, attempts have been made to improve retention of the ingredients on the ocular mucosa. For example, it is known that by adding a water-soluble polymer as a thickening agent or a thickening agent to an eye drop, retention of pharmacological components contained in the eye drop can be improved.

Cellulose-based polymers, which are a kind of water-soluble polymers, are partially decomposed by heat. Therefore, the viscosity of the composition containing the cellulosic polymer can decrease over time. There is known an ophthalmic solution in which a composition containing carboxymethyl cellulose (hereinafter also referred to as "CMC") is mixed with aspartic acid or a salt thereof to form a composition with reduced viscosity reduction (Patent Document 1).

JP 2006-104114

An object of the present invention is to provide novel eye drops containing brimonidine. An object of the present invention is to provide a novel ophthalmic solution containing a water-soluble polymer and having reduced viscosity reduction. Another object of the present invention is to provide a method or an agent for suppressing a decrease in viscosity of eye drops containing a water-soluble polymer.

The present inventors have made intensive research on components for suppressing viscosity reduction of eye drops containing CMC, and surprisingly found that brimonidine itself, an intraocular hypotensive agent, exhibits such a viscosity reduction inhibitory effect. Furthermore, by using BAK in combination, it was found that synergistically enhanced viscosity reduction suppressing action was exhibited, and the present invention was completed.

That is, the present invention relates to the following eye drops, method for suppressing viscosity decrease, and viscosity decrease inhibitor.

[Item 1] An ophthalmic solution containing brimonidine and/or a salt thereof, a water-soluble polymer, and benzalkonium chloride, wherein the content of brimonidine and/or a salt thereof is 0.05 w/v% to 0.2 w /v%, the content of the water-soluble polymer is 0.1w/v% to 1.5w/v%, and the content of benzalkonium chloride is 0.001w/v% to 0.01w/v %, and the weight ratio of brimonidine and/or its salt to benzalkonium chloride is 1:0.01 to 0.1.
[Item 2] The ophthalmic solution according to Item 1, wherein the weight ratio of brimonidine and/or a salt thereof to the water-soluble polymer and benzalkonium chloride is 1:1 to 15:0.01 to 0.1. .
[Item 3] The ophthalmic solution according to Item 1 or 2, wherein the water-soluble polymer is carboxymethylcellulose and/or a salt thereof.
[Item 4] The viscosity stability calculated by dividing the viscosity of the eye drop after storage at 60°C for 4 weeks by the viscosity of the eye drop before storage for 4 weeks is 90% or more. Item 4. The ophthalmic solution according to any one of Items 1 to 3.
[Item 5] The ophthalmic solution according to any one of Items 1 to 4, which has a pH of 6.7 to 7.5.
[Item 6] The ophthalmic solution according to any one of Items 1 to 5, which is used for treating glaucoma.
[Item 7] A method for suppressing a decrease in the viscosity of an eye drop containing a water-soluble polymer, wherein either one or both of brimonidine and/or a salt thereof and benzalkonium chloride are allowed to coexist in the eye drop. The content of brimonidine and/or a salt thereof is 0.05 w/v% to 0.2 w/v%, and the content of the water-soluble polymer is 0.1 w/v% to 1.5 w/v % and the content of benzalkonium chloride is 0.001 w/v % to 0.01 w/v %.
[Item 8] A step of allowing both brimonidine and/or a salt thereof and benzalkonium chloride to coexist in an eye drop, and the weight ratio of brimonidine and/or a salt thereof to benzalkonium chloride is 1:0. Item 8. The method according to Item 7, wherein the ratio is from 0.01 to 0.1.
[Item 9] The method according to Item 8, wherein the weight ratio of brimonidine and/or its salt, water-soluble polymer and benzalkonium chloride is 1:1 to 15:0.01 to 0.1.
[Item 10] The method according to any one of items 7 to 9, wherein the eye drop has a pH of 6.7 to 7.5.
[Item 11] The method according to any one of Items 7 to 10, wherein the water-soluble polymer is carboxymethylcellulose and/or a salt thereof.
[Item 12] A viscosity containing brimonidine and/or a salt thereof and benzalkonium chloride at a weight ratio of 1:0.01 to 0.1 for suppressing a decrease in the viscosity of an eye drop containing a water-soluble polymer. Decrease inhibitor.
[Item 13] Item 12, wherein the weight ratio of brimonidine and/or its salt, water-soluble polymer, and benzalkonium chloride is 1:1 to 15:0.01 to 0.1. Viscosity reduction inhibitor according to .
[Item 14] The viscosity reduction inhibitor according to Item 12 or 13, wherein the water-soluble polymer is carboxymethylcellulose and/or a salt thereof.
[Item 15]
An eye drop containing brimonidine and/or a salt thereof, carboxymethylcellulose, and benzalkonium chloride,
The content of brimonidine and/or a salt thereof is 0.1 w/v%, the content of carboxymethylcellulose is 0.1 w/v% to 1.5 w/v%, and the content of benzalkonium chloride is 0 .001 w/v% to 0.01 w/v%,
The eye drop has a pH of 6.7 to 7.5, and is calculated by dividing the viscosity of the eye drop after storage at 60° C. for 4 weeks by the viscosity of the eye drop before storage for the 4 weeks. eye drops having a viscosity stability of 90% or more.
[Item 16]
A method for suppressing a decrease in the viscosity of an eye drop containing carboxymethylcellulose, comprising the step of allowing both brimonidine and/or a salt thereof and benzalkonium chloride to coexist in the eye drop, wherein
The content of brimonidine and/or a salt thereof is 0.1 w/v%,
The content of carboxymethyl cellulose is 0.1 w/v% to 1.5 w/v%,
The content of benzalkonium chloride is 0.001 w/v% to 0.01 w/v%,
The eye drop has a pH of 6.7 to 7.5, and the viscosity of the eye drop after storage at 60° C. for 4 weeks is divided by the viscosity of the eye drop before storage for the 4 weeks. A method, wherein the calculated viscosity stability is greater than or equal to 90%.

INDUSTRIAL APPLICABILITY According to the present invention, an eye drop containing a water-soluble polymer and having reduced viscosity reduction is provided. INDUSTRIAL APPLICABILITY According to the present invention, there is provided a method or an agent for suppressing viscosity reduction of eye drops containing a water-soluble polymer.

In the present invention, "glaucoma" is characterized by functional and structural abnormalities of the eye that have characteristic changes in the optic nerve and visual field and that can improve or suppress optic nerve damage by sufficiently lowering intraocular pressure. Primary open-angle glaucoma, normal-tension glaucoma, hyperaqueous glaucoma, ocular hypertension, acute angle-closure glaucoma, chronic angle-closure glaucoma, mixed glaucoma, steroid glaucoma, amyloid glaucoma, vascular It includes neoglaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrome, and the like.

The "water-soluble polymer" is not particularly limited as long as it is commonly used as a thickener or thickening agent in eye drops, such as carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, carboxyvinyl polymer. (crosslinked polyacrylic acid polymer, etc.), xanthan gum, sodium chondroitin sulfate, sodium hyaluronate, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. Preferred water-soluble polymers in the eye drops of the present invention are cellulosic polymers and/or salts thereof. Examples of cellulosic polymers and/or salts thereof include carboxymethylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and salts thereof. Carboxymethylcellulose and/or salts thereof are particularly preferred water-soluble polymers in the eye drops of the present invention. These water-soluble polymers may be used singly or in combination of two or more.

"Carboxymethyl cellulose (CMC) and/or its salt" is commercially available, specifically, for example, NS-300, ECG-505 (manufactured by Gotoku Yakuhin Co., Ltd.), Sunrose (Nippon Paper Chemicals Co., Ltd.) (manufactured by Daiichi Kogyo Seiyaku Co., Ltd.), Ac-Di-Sol (manufactured by Asahi Kasei Chemicals Co., Ltd.), Kikkolate ND-2HS (manufactured by Nichirin Chemical Industry Co., Ltd.), and the like. Salts of CMC include, but are not limited to, sodium salts. In one embodiment, the salt of CMC is sodium carboxymethylcellulose. Either one of CMC and its salt may be used alone, or these may be used in combination. In this specification, references to the content or concentration of CMC and/or salts thereof mean the content or concentration in terms of sodium carboxymethylcellulose, unless otherwise specified.

Water-soluble polymers are used as, but not limited to, thickeners or thickeners to impart desired viscosity to eye drops. In one embodiment, the water-soluble polymer (e.g., CMC and/or a salt thereof) is used in an amount such that the eye drop has a viscosity of 1.0 mPa s or more and less than 30 mPa s at 25°C and a rotational speed of 60 rpm, Added to eye drops. The water-soluble polymer is preferably 1.0 mPa s or more and less than 15 mPa s, 1.5 mPa s or more and less than 5.0 mPa s, 1.5 mPa s or more, and 3 It is blended in an amount that gives a viscosity of less than 0 mPa·s.

In one embodiment, the concentration of water-soluble macromolecules (eg CMC and/or salts thereof) is 0.1 w/v % to 1.5 w/v % per eye drop volume, preferably 0.3 w/v. % to 0.7 w/v %.

In other embodiments, the eye drops comprise CMC and/or salts thereof as a thickening or thickening agent and are substantially free of other thickening or thickening agents.

"Brimonidine" is a selective adrenergic α2 receptor agonist and is compounded as an active ingredient in the ophthalmic solution of the present invention. Brimonidine and its salts are commercially available. Salts of brimonidine include, but are not limited to, tartrate, hydrochloride or acetate. In one embodiment, the salt of brimonidine is brimonidine tartrate. In this specification, references to a content or concentration of brimonidine and/or salts thereof mean a content or concentration in terms of brimonidine tartrate, unless otherwise specified.

In one embodiment, brimonidine and/or a salt thereof are not limited, but the water-soluble polymer (e.g., cellulose-based polymer, CMC as an example) contained in the eye drops is decomposed or denatured by heat, It is blended as one component of a viscosity decrease inhibitor for suppressing the accompanying decrease in the viscosity of the eye drops. The concentration of brimonidine and/or its salts is 0.05 w/v % to 0.2 w/v %, preferably 0.07 w/v % to 0.15 w/v %, more preferably 0.09 w per volume of eye drop. /v% to 0.12 w/v%.

In one embodiment, the eye drops may contain, in addition to brimonidine and/or a salt thereof, other pharmacological ingredients showing a therapeutic effect on glaucoma within a range that does not interfere with the effects of the present invention. Such other pharmacological components include, for example, prostaglandins such as tafluprost, latanoprost, and isopropyl unoprostone; parasympathomimetic agents such as pilocarpine hydrochloride; anticholinesterase agents such as distigmine bromide; β-blockers such as timolol maleate; β1-blockers such as betaxolol hydrochloride; α1/β-blockers such as nipradilol and levonolol hydrochloride; and α1-blockers such as bunazosin hydrochloride.

In one embodiment, the eye drops contain brimonidine and/or a salt thereof as a direct active ingredient against glaucoma and are substantially free of other active ingredients.

"Benzalkonium chloride (BAK)" is a quaternary ammonium component and is incorporated as a preservative in the eye drops of the present invention. BAK is commercially available. In one embodiment, BAK is, but is not limited to, a water-soluble polymer (e.g., a cellulose-based polymer, such as CMC) incorporated in an eye drop that is decomposed or denatured by heat, resulting in It is blended as one component of a viscosity decrease inhibitor for suppressing a decrease in the viscosity of. In one embodiment, the concentration of BAK is 0.001 w/v % to 0.01 w/v %, preferably 0.002 w/v % to 0.007 w/v %, more preferably 0.002 w/v %, per eye drop volume. .002 w/v% to 0.005 w/v%.

In one embodiment, the eye drops may further contain preservatives or preservatives commonly used for eye drops, in addition to BAK, as long as the effects of the present invention are not impaired. Such preservatives or preservatives include, but are not limited to, sorbic acid or salts thereof, benzoic acid or salts thereof, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, chlorobutanol, chlorhexidine gluconate. chlorhexidine hydrochloride, chlorhexidine acetate, boric acid or its salts, dehydroacetic acid or its salts, benzethonium chloride, benzyl alcohol, zinc chloride, para-chlormetaxylenol, chlorcresol, phenethyl alcohol, polydronium chloride, thimerosal, dibutyl hydroxy Toluene is mentioned. These additional preservatives or preservatives may be used singly or in combination of two or more.

In one embodiment, the eye drops contain BAK as a preservative or preservative and are substantially free of other preservatives or preservatives.

In one embodiment, the weight ratio of brimonidine and/or salts thereof to BAK is 1:0.01-0.1, preferably 1:0.02-0.07, more preferably 1: 0.02 to 0.05.

In one embodiment, the weight ratio of brimonidine and/or a salt thereof, a water-soluble polymer (such as CMC and/or a salt thereof), and BAK is 1:1-15:0.01-0.1 , preferably 1:2-10:0.02-0.07, more preferably 1:3-7:0.02-0.05.

In one embodiment, eye drops optionally contain a buffering agent to provide buffering. Buffers include, but are not limited to, phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, Tris buffers, amino acids. These buffering agents may be used singly or in combination of two or more. In one embodiment, the buffer is a borate buffer, preferably a combination of boric acid and sodium borate.

The buffering agent is included in an amount generally used, but not limited to, to provide sufficient buffering capacity to eye drops. In one embodiment, the buffering agent is boric acid, and its content is, for example, 0.01-5 w/v%, preferably 0.05-1 w/v%, more preferably 0.1-0.5w. /v%.

The eye drops may further contain optional additives such as a chelating agent and a cooling agent, if necessary, in addition to the above ingredients.

Chelating agents include, but are not limited to, edetate, citric acid or salts thereof. These chelating agents may be used singly or in combination of two or more.

Cooling agents include, but are not limited to, l-menthol, borneol, camphor, eucalyptus oil. These cooling agents may be used singly or in combination of two or more.

In the present invention, "eye drops" are aqueous compositions. Eye drops can be prepared according to a conventional method. Eye drops are not limited, but can be prepared by dissolving a water-soluble polymer in purified water and dissolving the aqueous solution in purified water together with the solid components. The pH of the prepared aqueous solution may be appropriately adjusted using hydrochloric acid or sodium hydroxide. Eye drops may be sterilized according to a conventional method and then filled into product containers. In one embodiment, the sterilization process is filter filtration.

In one embodiment, the eye drops have a pH of 6.7-7.5 and an osmolality of 250-350 milliosmoles. In other embodiments, the eye drops have a pH of 6.7-7.3 and an osmotic ratio of 0.85-1.15. In other embodiments, the eye drops preferably have a pH of 7.1 and an osmotic ratio of about 1.0. "About" with respect to osmotic ratio means ±0.1, and osmotic ratio of about 1.0 indicates between 0.9 and 1.1. Osmolality is adjusted according to routine methods. In one embodiment, the osmotic pressure is adjusted by adding a pharmaceutically acceptable salt as a tonicity agent to the eye drops. Pharmaceutically acceptable salts include, but are not limited to, magnesium chloride, sodium chloride, potassium chloride, calcium chloride and hydrates thereof.

As used herein, the "viscosity" of eye drops is measured according to the method of viscosity measurement, method 2, rotational viscometer, which is defined in the General Test Methods of the Japanese Pharmacopoeia, as described in the Examples. The viscosity of the eye drops after preparation is appropriately set according to the purpose of use. The viscosity of the eye drops is, but not limited to, 1.0 mPa·s or more and less than 30 mPa·s at 25° C. and a rotational speed of 60 rpm. In one embodiment, the eye drop after preparation has a viscosity of 1.0 mPa·s or more and less than 15 mPa·s at 25° C. and a rotational speed of 60 rpm. In one embodiment, the viscosity at 25° C. of the eye drop after preparation is 1.5 mPa·s or more and less than 5.0 mPa·s, or 1.5 mPa·s or more and less than 3.0 mPa·s.

The viscosity of the eye drops is imparted by, but not limited to, the incorporated water-soluble polymer. In one embodiment, the viscosity of the eye drops is adjusted by the amount of water-soluble polymer (eg, cellulosic polymer) or substantially only CMC and/or salts thereof. In other embodiments, the viscosity of the eye drops is adjusted by combining CMC and/or salts thereof with other water-soluble polymers described herein.

As used herein, the term “viscosity stability” refers to filling an eye drop into a glass ampoule, storing it in a thermostat at 60° C. for 4 weeks, and measuring the stability of the aqueous solution after storage. It is calculated by dividing the viscosity by the viscosity of the aqueous liquid formulation before storage (=viscosity of aqueous liquid formulation after storage [mPa·s]/viscosity of aqueous liquid formulation before storage [mPa·s]×100). In one embodiment, the viscosity stability is 90% or greater, preferably 92% or greater, more preferably 94% or greater.

As used herein, "viscosity reduction suppression" refers to the viscosity stability when one or both of brimonidine and/or a salt thereof and BAK are blended in an eye drop containing a water-soluble polymer. Or it means that the viscosity stability is higher than when neither its salt nor BAK is blended. In one embodiment, the degree of viscosity reduction suppression is determined by the viscosity stability of a water-soluble polymer (e.g., CMC)-containing eye drop containing brimonidine and/or a salt thereof and BAK, and the The difference from the viscosity stability of the same water-soluble polymer-containing ophthalmic solution except that it does not contain is 4% or more, 5% or more, 6% or more, or 7% or more.

In one embodiment, the eye drops are for treating glaucoma. As used herein, "treatment" means alleviation, alleviation of symptoms, or slowing of progression. In one embodiment, the eye drops contain an amount of brimonidine and/or a salt thereof effective for treating glaucoma, and do not contain other pharmacological ingredients as pharmacological ingredients.

Eye drops are instilled in, but are not limited to, single drops, once or multiple times per day. In one embodiment, the eye drops are instilled one drop twice daily. Concentrations of each component in the eye drops are appropriately set according to the usage and dosage.

A first aspect of the present invention relates to eye drops comprising a water-soluble polymer, brimonidine and/or salts thereof, and BAK. In one embodiment, the eye drops contain 0.05 w/v % to 0.2 w/v % of brimonidine and/or a salt thereof, a water-soluble polymer (eg, a cellulosic polymer such as CMC and/or its salt). salt) from 0.1 w/v% to 1.5 w/v% and BAK from 0.001 w/v% to 0.01 w/v%, and the weight ratio of brimonidine and/or its salt to BAK is 1 : 0.01 to 0.1.

In another embodiment, the eye drops contain 0.07% w/v to 0.15% w/v of brimonidine tartrate (preferably 0.09% to 0.12% w/v, more preferably 0.1% w/v). /v%), CMC from 0.3 w/v% to 0.7 w/v% (preferably 0.5 w/v%), and BAK from 0.001 w/v% to 0.01 w/v% (preferably 0.002 w/v% to 0.007 w/v%, more preferably 0.002 w/v% to 0.005 w/v%), and the weight ratio of brimonidine tartrate to benzalkonium chloride is 1: 0.01 to 0.1 (preferably 1:0.02 to 0.07, more preferably 1:0.02 to 0.05), further containing boric acid and borax (osmotic pressure ratio: 0 .9-1.1 (ie about 1.0), pH: 6.7-7.5).

In other embodiments, the eye drops comprise at least one cellulosic polymer and/or salt thereof (e.g., CMC and/or salt thereof) as a thickener or thickening agent, and substantially no other thickening agent. It contains brimonidine and/or a combination of its salts and BAK as a viscosity-lowering inhibitor and is substantially free of other viscosity-lowering inhibitors.

A second aspect of the present invention comprises a step of coexisting either one or both of brimonidine and/or a salt thereof and BAK in an eye drop containing a water-soluble polymer (e.g., CMC and/or a salt thereof). More preferably, both brimonidine and/or a salt thereof and BAK are added to an eye drop containing a water-soluble polymer (e.g., CMC and/or a salt thereof). It relates to a method for suppressing viscosity reduction of eye drops, including coexistence. The method is not particularly limited, and for example, it is carried out by blending brimonidine and/or a salt thereof and BAK into the eye drops. The order of addition of each component is not particularly limited. Each component in the formulation may be, but is not limited to, solid or liquid.

In one embodiment, the weight ratio of brimonidine and/or its salt and BAK to be blended is 1:0.01 to 0.1, preferably 1:0.02 to 0.07, more preferably 1 : 0.02 to 0.05. In one embodiment, the weight ratio of brimonidine and/or a salt thereof, CMC and/or a salt thereof, and BAK to be blended is 1:1 to 15:0.01 to 0.1, preferably 1 : 2-10: 0.02-0.07, more preferably 1:3-7: 0.02-0.05.

In one embodiment, an eye drop in which brimonidine and/or a salt thereof, a water-soluble polymer, and BAK coexist has 0.05 w/v% to 0.2 w of brimonidine and/or a salt thereof per eye drop volume. /v%, CMC and/or salts thereof at 0.1 w/v% to 1.5 w/v% per eye drop volume, and BAK at 0.001 w/v% to 0.01 w/v% per eye drop volume. do.

A third aspect of the present invention is to suppress a decrease in the viscosity of eye drops containing a water-soluble polymer containing brimonidine and/or a salt thereof and BAK at a weight ratio of 1:0.01 to 0.1. relates to a viscosity reduction inhibitor. In one embodiment, the weight ratio of brimonidine and/or its salt and BAK blended in the viscosity reduction inhibitor is 1: 0.02 to 0.07, preferably 1: 0.02 to 0.05. be.

In one embodiment, the viscosity reduction inhibitor is blended based on the content of the water-soluble polymer (e.g., CMC and/or a salt thereof) in the eyedrops containing the viscosity reduction inhibitor. The weight ratio of brimonidine and/or a salt thereof, a water-soluble polymer and BAK in the eye drops after application is 1:1-15:0.01-0.1, preferably 1:2-10:0. 02 to 0.07, more preferably 1:3 to 7:0.02 to 0.05. Viscosity reduction inhibitors may be in, but are not limited to, liquid or solid (eg, powder or tablet) form. The powder or tablet can be produced by a conventional method.

A fourth aspect of the present invention is 0.05 w/v% to 0.2 w/v% brimonidine and/or a salt thereof, 0.1 w/v% to 1.5 w/v% water-soluble polymer, and The present invention relates to a method for producing eye drops, comprising mixing 0.001 w/v% to 0.01 w/v% BAK with a pharmaceutically acceptable aqueous medium. "Pharmaceutically acceptable aqueous medium" means an aqueous medium that can be used for topical application to the eye and can be, but is not limited to, purified water. In one embodiment, the blending step may blend an aqueous polymer (eg, CMC) and purified water, then blend brimonidine and/or its salts, and BAK. The manufacturing method may further include, but is not limited to, the step of incorporating additional additive ingredients. The manufacturing method may further include, but is not limited to, a sterilization step. In one embodiment, the sterilization process is filter filtration.

Each element referred to in this specification, such as water-soluble polymer (e.g., CMC and/or its salt) to be formulated, concentration of BAK and brimonidine in eye drops, viscosity of eye drops, viscosity stability, optional additive components , pH, osmotic pressure, etc. in eye drops apply to each element relating to the first to fourth aspects. Numerical ranges recited herein are inclusive of their upper and lower values, unless explicitly stated as "greater than" or "less than."

[Preparation of eye drops]
Aqueous solutions were prepared according to the formulations shown in Table 1. Each aqueous solution was made isotonic by adding appropriate amounts of sodium chloride, potassium chloride, calcium chloride hydrate and magnesium chloride, and adjusted to pH 7.0 using hydrochloric acid or sodium hydroxide.

[Accelerated deterioration test]
A 5 mL colorless glass ampoule was filled with 5 mL of the aqueous solution filtered through a 0.22 μm filter. Each glass ampoule was placed in a thermostat (CH-M20-01, Nagano Science Co., Ltd.) and stored at 60° C. for 4 weeks under light-shielding conditions.

[Viscosity measurement]
The viscosity [mPa s] of the aqueous liquid agent is determined by the Japanese Pharmacopoeia general test method Viscosity measurement method 2 Rotational viscometer method (cone-plate rotational viscometer (cone-plate viscometer, TVE-20L, Toki Sangyo Co., Ltd.)) at 25° C. and a rotational speed of 60 rpm. Viscosity measurements were performed before and after the accelerated aging test. The viscosity stability (%) of the aqueous solution was calculated according to the following formula.
(Number 1)
Viscosity stability [%] = Viscosity of aqueous solution after storage [mPa s] / Viscosity of aqueous solution before storage [mPa s] × 100

[Test results]
The viscosity of the aqueous solution of Formulation 1 was 2.513 [mPa·s] before the accelerated deterioration test, and 2.370 [mPa·s] after the accelerated test. The viscosity stability was 94.3[%].
Similarly, the viscosity stability of Formulations 2, 3 and 4 was calculated.
Prescription 2: 90.8 [%] (= 2.399 [mPa s] / 2.641 [mPa s] × 100);
Prescription 3: 87.4 [%] (= 2.213 [mPa s] / 2.531 [mPa s] × 100), and Prescription 4: 86.5 [%] (= 2.173 [mPa s] / 2.513 [mPa・s] × 100).

Table 2 summarizes the test results and ingredient combinations for Formulations 1-4.

Aqueous solutions containing 0.5 w/v % sodium carboxymethylcellulose showed less than 90% viscosity stability when stored at 60° C. for 4 weeks (formulation 3). An aqueous solution in which 0.005 w/v% BAK was further blended with the aqueous solution component of formulation 3 also showed less than 90% viscosity stability (formulation 4). This suggests that the incorporation of BAK has little effect on the viscosity stability of aqueous solutions containing sodium carboxymethylcellulose (formulations 3 and 4).

An aqueous solution in which 0.1 w/v % brimonidine tartrate was additionally blended with the aqueous solution component of Formulation 3 exhibited viscosity stability greater than 90% (Formulation 2). This suggests that the incorporation of brimonidine tartrate can improve the viscosity stability of aqueous solutions containing sodium carboxymethylcellulose (formulations 2 and 3).

An aqueous solution in which 0.1 w/v % brimonidine tartrate and 0.005 w/v % BAK were further blended with the aqueous solution components of Formulation 3 exhibited approximately 95% viscosity stability (Formulation 1). The extent of improvement in viscosity stability of aqueous solutions containing both brimonidine tartaric acid and BAK (Formulation 1 and Formulation 3) is the sum of the extent of improvement in viscosity stability of aqueous solutions containing either one of the above two components. values (Formulations 2-4). These results suggested that the combination of brimonidine tartrate and benzalkonium chloride synergistically improved the viscosity stability of the sodium carboxymethylcellulose-containing aqueous solution.

Claims (11)

An eye drop containing brimonidine and/or a salt thereof, a water-soluble polymer, and benzalkonium chloride, wherein the content of brimonidine and/or a salt thereof is 0.05 w/v% to 0.2 w/v% is, the content of the water-soluble polymer is 0.1 w/v% to 1.5 w/v%, the content of benzalkonium chloride is 0.001 w/v% to 0.01 w/v%, An eye drop having a weight ratio of brimonidine and/or a salt thereof and benzalkonium chloride of 1:0.01-0.1 and a pH of 6.7-7.0, but containing no timolol. 2. The ophthalmic solution according to claim 1, wherein said water-soluble polymer is a cellulosic polymer and/or a salt thereof. 3. The ophthalmic solution according to claim 1, wherein the weight ratio of brimonidine and/or its salt, water-soluble polymer and benzalkonium chloride is 1:1-15:0.01-0.1. The ophthalmic solution according to any one of claims 1 to 3, which has a pH of 6.7. The viscosity stability calculated by dividing the viscosity of the eye drop after storing the eye drop for 4 weeks at 60° C. by the viscosity of the eye drop before storing for 4 weeks is 90% or more. 5. The ophthalmic solution according to any one of 1 to 4. The ophthalmic solution according to any one of claims 1 to 5, which is for treating glaucoma. A method for suppressing a decrease in viscosity of an eye drop containing a water-soluble polymer, comprising the step of allowing both brimonidine and/or a salt thereof and benzalkonium chloride to coexist in the eye drop, wherein brimonidine and/or The salt content is 0.05 w/v% to 0.2 w/v%, the water-soluble polymer content is 0.1 w/v% to 1.5 w/v%, and benzalkonium chloride content is 0.001 w/v % to 0.01 w/v % and pH is 6.7 to 7.0, provided that said eye drop does not contain timolol. 8. The method according to claim 7, wherein the water-soluble polymer is a cellulosic polymer and/or its salt. The method according to claim 7 or 8, wherein the weight ratio of brimonidine and/or its salts and benzalkonium chloride is 1:0.01-0.1. The weight ratio of brimonidine and/or its salt, water-soluble polymer, and benzalkonium chloride is 1:1 to 15:0.01 to 0.1, according to any one of claims 7 to 9 described method. A method according to any one of claims 7 to 10, wherein the pH is 6.7.